Adhesion failures determine the pattern of choroidal neovascularization in the eye: a computer simulation study.
Adhesion failures determine the pattern of choroidal neovascularization in the eye: a computer simulation study.
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DOI：
10.1371/journal.pcbi.1002440
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发表时间：
2012
影响因子：
4.3
通讯作者：
Grossniklaus HE
中科院分区：
文献类型：
--
作者：
Shirinifard A;Glazier JA;Swat M;Gens JS;Family F;Jiang Y;Grossniklaus HE
Choroidal neovascularization (CNV) of the macular area of the retina is the major cause of severe vision loss in adults. In CNV, after choriocapillaries initially penetrate Bruch's membrane (BrM), invading vessels may regress or expand (CNV initiation). Next, during Early and Late CNV, the expanding vasculature usually spreads in one of three distinct patterns: in a layer between BrM and the retinal pigment epithelium (sub-RPE or Type 1 CNV), in a layer between the RPE and the photoreceptors (sub-retinal or Type 2 CNV) or in both loci simultaneously (combined pattern or Type 3 CNV). While most studies hypothesize that CNV primarily results from growth-factor effects or holes in BrM, our three-dimensional simulations of multi-cell model of the normal and pathological maculae recapitulate the three growth patterns, under the hypothesis that CNV results from combinations of impairment of: 1) RPE-RPE epithelial junctional adhesion, 2) Adhesion of the RPE basement membrane complex to BrM (RPE-BrM adhesion), and 3) Adhesion of the RPE to the photoreceptor outer segments (RPE-POS adhesion). Our key findings are that when an endothelial tip cell penetrates BrM: 1) RPE with normal epithelial junctions, basal attachment to BrM and apical attachment to POS resists CNV. 2) Small holes in BrM do not, by themselves, initiate CNV. 3) RPE with normal epithelial junctions and normal apical RPE-POS adhesion, but weak adhesion to BrM (e.g. due to lipid accumulation in BrM) results in Early sub-RPE CNV. 4) Normal adhesion of RBaM to BrM, but reduced apical RPE-POS or epithelial RPE-RPE adhesion (e.g. due to inflammation) results in Early sub-retinal CNV. 5) Simultaneous reduction in RPE-RPE epithelial binding and RPE-BrM adhesion results in either sub-RPE or sub-retinal CNV which often progresses to combined pattern CNV. These findings suggest that defects in adhesion dominate CNV initiation and progression. This paper tests hypotheses for the mechanisms of choroidal neovascularization (CNV), the pathological growth of capillaries in response to physical defects in a structured tissue, the retina, showing that previously neglected cell-cell, cell-ECM and ECM-ECM adhesion failures suffice to determine the loci and progression of neovascularization. Surprisingly, a simple theory based on classes of adhesion failures, which involve variation of only five parameters, can coherently explain the heterogeneous range of CNV growth patterns and dynamics. Our results are generally applicable to other types of tissues where capillaries are close to an epithelium, e.g., lung and gut.
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影响因子：
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作者：
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通讯作者：
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